A genomic structural equation modelling analysis of the shared genetic architecture of the aging spine.

BACKGROUND

Clinical manifestations of aging spine, such as lumbar spinal stenosis, intervertebral disc degeneration, osteoporosis and sciatica, frequently co-occur, yet their shared genetic basis remains unclear.

METHODS

We assembled large-scale GWAS summary statistics for telomere length, osteoporosis, intervertebral disc degeneration, lumbar spinal stenosis and sciatica, and applied Genomic structural equation modelling to model their SNP-based heritability and genetic covariance structure. A latent aging spine factor was fitted to capture common genetic liability, followed by mvGWAS of the factor, fine-mapping, MAGMA, SCCA-TWAS with FOCUS, pathway, cell-type and functional enrichment analysis.

RESULTS

All five traits showed non zero SNP based heritability and a coherent pattern of genetic covariance, and were well summarized by a single latent aging spine factor that loaded most strongly on lumbar spinal stenosis, sciatica and intervertebral disc degeneration. GWAS of this factor identified 273 independent lead variants, and fine mapping highlighted a focused set of putatively causal SNPs, such as rs61981103, rs111736973 and rs963278. Integrative TWAS and MAGMA analysis converged on susceptibility genes such as LRRC34, MYNN, SAMHD1 and EEF1A2. Enrichment analysis consistently implicated telomere biology, chromosome maintenance and genomic stability pathways.

CONCLUSIONS

These findings support the aging spine as a biologically meaningful construct with a shared genetic basis, and provide an initial map of its polygenic architecture that extends previous single-trait studies.